Presented at the Annual Meeting of the American Society of Clinical Oncology, Moscone Convention Center, San Francisco, California, May 21-23, 1989. 

"Interaction of Ribothymidine and Thymidine within Human Phytohemagglutinin-Activated Killer T-Lymphocytes."

John H. Frenster, M.D.

Departments of Medicine
Stanford University and Santa Clara Valley Medical Center
San Jose, California 95128

Human T-lymphocytes can be activated to cell mitosis by phytohemagglutinin (PHA)in preparation for in-vivo immunotherapy trials in donor cancer patients (Frenster JH, Ann. N.Y. Acad. Sci. 277, p. 45 (1976). Such PHA-activated killer lymphocytes were incubated in culture for up to 120 hours after addition of PHA, and metaphases/1000 cells were counted in replicate cultures at 3 hour intervals in the presence of added ribothymidine or thymidine. At all tested concentrations, ribothymidine was ten times more inhibitory to cell mitosis than was thymidine. Low concentrations (0.05 x 10 -3 M) of thymidine were able to reverse the inhibitory effects of high concentrations (10 -3M) of ribothymidine, even after 8 hours of prior exposure to ribothymidine before the addition of thymidine, and in the continued presence of the high concentrations of ribothymidine. Added adenosine, deoxyadenosine, guanosine, or deoxyguanosine had no ability to reverse the inhibition induced by ribothymidine, but uridine, deoxyuridine, cytidine, and deoxycytidine had significant but lesser reversal ability than did thymidine. Reversal of ribothymidine inhibition was not complete until 15 hours after the addition of thymidine, confirming that ribothymidine exerts its inhibitory effect at or near the beginning of DNA synthesis in S phase. These data suggest that ribothymidine may bind to the pre-replicative DNA template, and that thymidine at low concentrations may displace such binding. Supported in part by Research Grants CA-10174 and CA-13524 from the National Cancer Institute, Research Grant IC-45 from the American Cancer Society, and by a Research Scholar Award from the Leukemia Society of America.

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